CYLD (cylindromatosis (turban tumor syndrome))

2010-05-01   Gilles Courtois 

INSERM U781, Hopital Necker-Enfants Malades, Paris, France




Atlas Image
Figure 1. CYLD gene. Coding exons are indicated in dark red. Asterisks indicate exons which are differentially spliced. One of the exon which is alternatively present (Reiley et al., 2004) encodes the binding site for TRAF2 and NEMO (Hövelmeyer et al., 2007).


21 exons (17 coding) with alternative splicing (see figure 1). Size of the exons: 74 (bp), 98, 79, 136, 626, 302, 105, 8, 98, 116, 379, 165, 141, 122, 91, 66, 132, 108, 118, 216, 5611. The whole gene extends over approximately 56 kb.




Atlas Image
Figure 2. Structural organisation of CYLD. Binding sites for TRAF2 and NEMO are indicated. CAP: CAP-Gly domain, P: phosphorylation site, C and H: subdomains of the catalytic domain containing the Cys and His active residues.


956 aa, approximately 110 kD.
Member of the deubiquitinase family (USP (Ubiquitin Specific Protease)) (Reyes-Turcu et al., 2009) with preferential affinity for K63-linked polyubiquitin chains (Massoumi and Paus, 2007; Courtois, 2008).




Cytoplasm (might bind to microtubules through its CAP-Gly domains).


CYLD has been primarily identified as a negative regulator of NF-kappaB signaling, able to bind NEMO and TRAF2 and to deubiquitinate them (Brummelkamp et al., 2003; Kovalenko et al., 2003; Trompouki et al., 2003). It is also a negative regulator of JNK and p38 signaling pathways (Reiley et al., 2004) and IRF-3 signaling pathways (Friedman et al., 2008; Zhang et al., 2008). It participates in antimicrobial defense and inflammation by targeting ubiquitinated TRAF6 (Lim et al., 2007; Lim et al., 2008) and is required for the development and activation of immune cells (Reiley et al., 2006; Jin et al., 2007). CYLD may also affect cell proliferation/cell cycling by targeting Plk1 and HDAC6 (Stegmeier et al., 2007; Massoumi et al., 2009) and cell migration via microtubule assembly (Gao et al., 2008). It controls spermatogenesis by deubiquitinating RIP (Wright et al., 2007) and osteoclastogenesis by deubiquitinating TAK1 (Jin et al., 2008). A role for CYLD in the hypoxia response has been reported (An et al., 2008). Its inactivation by human papilloma virus-derived E6 protein results in hypoxia-induced NF-kappaB activation. Finally, it has been shown to affect calcium channel function by deubiquitinating TRPA1 (Stokes et al., 2006).
CYLD interacts with NEMO (Kovalenko et al., 2003; Trompouki et al., 2003), TRAF2 (Kovalenko et al., 2003; Trompouki et al., 2003), p62 (Wooten et al., 2008), Bcl-3 (Massoumi et al., 2006), TAK1 (Reiley et al., 2007), RIP (Wright et al., 2007), lck (Reiley et al., 2006), HDAC6 (Wickström et al., 2010).


Catalytic box (with other members of the deubiquitinase family (USPs)) and CAP-Gly (with a small collection of proteins (Steinmetz and Akhmanova, 2008)).


Atlas Image
Figure 3. Mutations of CYLD. Misense mutations are indicated by boxes, nonsense mutations by black brackets and frameshift mutations by orange bars. Compiled from Blake and Toro, 2009 with additions from Amaro et al., 2009; Kazakov et al., 2009; Nasti et al., 2009; Wang et al., 2010 and Kazakov et al., 2010.


Tumor suppressor (Bignell et al., 2000).
See full recent listing in Blake and Toro, 2009. Most of the mutations (non sense, frameshit, splicing) would produce large deletions of the protein but, most likely, produce mRNA nonsense-mediated decay. Short truncations affect the catalytic box which extends to the carboxy-terminus of the protein and produce an inactive enzyme. Very few missense mutations have been reported. All of them affect the catalytic box.


Loss of heterozygosity in developing tumors.

Implicated in

Entity name
Familial cylindromatosis and multiple trichoepithelioma
Familial cylindromatosis, also called turban tumor syndrome is a rare inherited cancer which is characterized by the formation of benign tumors, called cylindroma, in hairy parts of the body, mostly the scalp. Cylindroma are considered as originating from a transformation event specifically affecting the folliculo-sebaceous-apocrine unit that produces hair and its associated glands. Early observations established that affected patients are heterozygous at birth for the locus causing the disease, whereas the cylindroma they develop exhibit a loss of heterozygosity (LOH) demonstrating the involvment of a gene coding for a tumor suppressor. More recently, it has been shown that another genetic disease sharing similarities with familial cylindromatosis, multiple trichoepithelioma (MT), is also caused by CYLD mutations (For reviews, see Massoumi and Paus, 2007; Courtois, 2008; Amaro et al., 2009).
Entity name
Various cancers
Loss of CYLD has been reported in solid tumors of the colon and liver (Hellerbrand et al., 2007), kidney (Ströbel et al., 2002), cervix (Hirai et al., 2004) and prostate (Kikuno et al., 2008). CYLD is also epigenetically silenced in some non-small-cell lung cancers (NSCLC) (Zhong et al., 2007).
In the case of melanoma, it has been shown that the CYLD promoter region is under negative control by snail, a protein which is upregulated in this disease (Massoumi et al., 2009). CYLD down-regulation results in Bcl3/NF-kappaB activation.


Pubmed IDLast YearTitleAuthors
199299392010Multiple trichoepitheliomas--a novel mutation in the CYLD gene.Amaro C et al
189773282008Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia-induced NF-kappaB activation.An J et al
176928042007Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.Annunziata CM et al
108356292000Identification of the familial cylindromatosis tumour-suppressor gene.Bignell GR et al
194624652009Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling.Blake PW et al
129176902003Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB.Brummelkamp TR et al
181931682008Tumor suppressor CYLD: negative regulation of NF-kappaB signaling and more.Courtois G et al
186360862008The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response.Friedman CS et al
182229232008The tumor suppressor CYLD regulates microtubule dynamics and plays a role in cell migration.Gao J et al
167749472007Reduced expression of CYLD in human colon and hepatocellular carcinomas.Hellerbrand C et al
150108382004Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix.Hirai Y et al
179234992007Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD.Hövelmeyer N et al
176094262007Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma.Jenner MW et al
183827632008Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice.Jin W et al
173922862007Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells.Jin W et al
201324222010Brooke-Spiegler syndrome: report of a case with a novel mutation in the CYLD gene and different types of somatic mutations in benign and malignant tumors.Kazakov DV et al
176928052007Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.Keats JJ et al
184317422008Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells.Kikuno N et al
129176912003The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination.Kovalenko A et al
186439242008CYLD is a crucial negative regulator of innate immune response in Escherichia coli pneumonia.Lim JH et al
179258802007Tumor suppressor CYLD acts as a negative regulator for non-typeable Haemophilus influenza-induced inflammation in the middle ear and lung of mice.Lim JH et al
191246562009Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma.Massoumi R et al
198077422009Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas.Nasti S et al
154964002004Negative regulation of JNK signaling by the tumor suppressor CYLD.Reiley W et al
175485202007Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses.Reiley WW et al
165015692006Regulation of T cell development by the deubiquitinating enzyme CYLD.Reiley WW et al
194897242009Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes.Reyes-Turcu FE et al
174950262007The tumor suppressor CYLD regulates entry into mitosis.Stegmeier F et al
188357172008Capturing protein tails by CAP-Gly domains.Steinmetz MO et al
165000802006TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD.Stokes A et al
117567792002Spiradenocylindroma of the kidney: clinical and genetic findings suggesting a role of somatic mutation of the CYLD1 gene in the oncogenesis of an unusual renal neoplasm.Ströbel P et al
129176892003CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members.Trompouki E et al
199111862010A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma.Wang FX et al
198934912010CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin.Wickström SA et al
181741612008Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins.Wooten MW et al
179811382007Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD.Wright A et al
184673302008Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD.Zhang M et al
170436442007Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer.Zhong S et al

Other Information

Locus ID:

NCBI: 1540
MIM: 605018
HGNC: 2584
Ensembl: ENSG00000083799


dbSNP: 1540
ClinVar: 1540
TCGA: ENSG00000083799


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
RIG-I-like receptor signaling pathwayKEGGko04622
RIG-I-like receptor signaling pathwayKEGGhsa04622
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
NOD1/2 Signaling PathwayREACTOMER-HSA-168638
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathwaysREACTOMER-HSA-168928
Negative regulators of RIG-I/MDA5 signalingREACTOMER-HSA-936440
Signal TransductionREACTOMER-HSA-162582
Death Receptor SignallingREACTOMER-HSA-73887
TNF signalingREACTOMER-HSA-75893
TNFR1-induced proapoptotic signalingREACTOMER-HSA-5357786
TNFR1-induced NFkappaB signaling pathwayREACTOMER-HSA-5357956
Regulation of TNFR1 signalingREACTOMER-HSA-5357905
Ub-specific processing proteasesREACTOMER-HSA-5689880

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
129176912003The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination.334
207976232010STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer.333
129176892003CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members.299
129176902003Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB.299
220374142011Caspase 8 inhibits programmed necrosis by processing CYLD.169
167135612006Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling.167
186360862008The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response.135
183133832008The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module.98
194815262009Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKKepsilon promotes cell transformation.94
208327542010The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia.93


Gilles Courtois

CYLD (cylindromatosis (turban tumor syndrome))

Atlas Genet Cytogenet Oncol Haematol. 2010-05-01

Online version: